5-(4-Fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide (I) is a key intermediate in the synthesis of atorvastatin calcium (LIPITOR®), known also by the chemical name [R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (2:1) trihydrate. Atorvastatin calcium inhibits 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and thus is useful as a hypolipidemic and/or hypocholesterolemic agent.

A number of patents have issued disclosing atorvastatin, as well as processes and key intermediates for preparing atorvastatin. These include: U.S. Pat. Nos. 4,681,893, 5,273,995, 5,003,080; 5,097,045, 5,103,024, 5,124,482, 5,149,837, 5,155,251, 5,216,174, 5,245,047, 5,248,793, 5,280,126, 5,397,792, 5,342,952, 5,298,627, 5,446,054, 5,470,981, 5,489,690, 5,489,691, 5,510,488, 5,998,633, 6,087,511, 5,969,156, 6,121,461, 5,273,995 6,476,235, 5,969,156, and 6,121,461.
Existing approaches to the preparation of key intermediate (I) presented some shortcomings. For example, one approach relied on the use of a costly chiral raw material ((R)-4-cyano-3-hydroxy-butyric acid ethyl ester), and a low temperature diastereoselective borane reduction.
Scheme 1 summarizes an alternative approach disclosed in U.S. Pat. No. 6,476,235. Hydrogenation of β,δ diketoacid 2 in the presence of a chiral ruthenium catalyst under acidic conditions proceeded to give diol 3 in moderate to good yields and 1:1 syn:anti diastereoselectivity with respect to the C-3 and C-5 chiral centers. A number of additional transformations are then necessary to reset the stereochemistry of the C-3 center in diol 3 to provide key intermediate (I). These steps include: (a) intramolecular cyclization of 3 to provide lactone 4; (b) elimination of water from lactone 4 to provide α,β unsaturated lactone 5; (c) facial selective Michael addition of allyl or benzyl alcohol to α,β unsaturated lactone 5 to provide saturated lactone 6; and removal of the allyl or benzyl moiety in lactone 6 via hydrogenolysis provided key intermediate (I).

As a preliminary matter, the asymmetric hydrogenation of ketones is a known transformation in organic synthesis. However, the complexity of the reaction increases in the case of 1,3,5-tricarbonyl systems, and poor yields and poor stereoselectivities often result. In fact, investigations by Saburi. (Tetrahedron, 1997, 1993;49) and Carpentier (Eur. J. Org. Chem. 1999;3421) have independently demonstrated low to moderate diastereo- and/or enantio-selectivities for diketoester asymmetric hydrogenations.
Furthermore, the fact that the processes disclosed in the literature require high pressure hydrogenation and extended reaction times makes the procedures generally impractical and not amenable to large-scale manufacturing processes where safety, efficiency, and cost are critical considerations.
As a result, a need remains for an approach to the preparation of key intermediate (I) that is efficient, inexpensive, proceeds in a minimum of transformations, and occurs in good yield and high levels of diastereoselectivity.